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Discovery of Procognitive Antipsychotics by Combining Muscarinic M-1 Receptor Structure-Activity Relationship with Systems Response Profiles in Zebrafish Larvae

Artikel i vetenskaplig tidskrift
Författare K. Hellman
J. Ohlsson
Marcus Malo
Roger Olsson
F. Ek
Publicerad i ACS Chemical Neuroscience
Volym 11
Nummer/häfte 2
Sidor 173-183
ISSN 1948-7193
Publiceringsår 2020
Publicerad vid Institutionen för kemi och molekylärbiologi
Sidor 173-183
Språk en
Länkar dx.doi.org/10.1021/acschemneuro.9b0...
Ämnesord Zebrafish, antipsychotics, muscarinic agonist, structure-activity, relationship, N-desmethylclozapine, behavioral profiling, n-desmethylclozapine, allosteric modulation, drug, schizophrenia, clozapine, m1, identification, association, impairment, activation, Biochemistry & Molecular Biology, Pharmacology & Pharmacy, Neurosciences, & Neurology
Ämneskategorier Biokemi och molekylärbiologi

Sammanfattning

Current antipsychotic drugs are notably ineffective at addressing the cognitive deficits associated with schizophrenia. N-Desmethylclozapine (NDMC), the major metabolite of clozapine, displays muscarinic M-1 receptor (M-1) agonism, an activity associated with improvement in cognitive functioning. Preclinical and clinical data support that M-1 agonism may be a desired activity in antipsychotic drugs. However, NDMC failed clinical phase II studies in acute psychotic patients. NDMC analogues were synthesized to establish a structure-activity relationship (SAR) at the M-1 receptor as an indication of potential procognitive properties. In vitro evaluation revealed a narrow SAR in which M-1 agonist activity was established by functionalization in the 4- and 8-positions in the tricyclic core. In vivo behavioral response profiles were used to evaluate antipsychotic efficacy and exposure in zebrafish larvae and peripheral side effect related M-1 activity in adult zebrafish. The NDMC analogue 13f demonstrated antipsychotic activity similar to clozapine including M-1 agonist activity. Cotreatment with trospium chloride, an M1 peripheral acting antagonist, counteracted peripheral side effects. Thus, the NDMC analogue 13f, in combination with a peripherally acting anticholinergic compound, could be suitable for further development as an antipsychotic compound with potential procognitive activity.

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